Background
Hand, foot, and mouth disease (HFMD), an infectious disease caused by several human enteroviruses, primarily affects the physical and mental health of children less than 5 years of age [
1]. One of the notable routes of HFMD transmission is through respiratory secretions [
2], as patients have a relatively strong ability to transmit enteroviruses to the environment and other vulnerable populations. Over the last few decades, HFMD has become a prominent public health problem in numerous countries in the Asia–Pacific region [
3,
4]. The HFMD disease burden remains high, especially in China. The annual reported number of HFMD cases has reached 1.61 to 2.77 million [
5]. To date, there are no specific antienterovirus agents administered for HFMD. Since 2016, three EV-A71 vaccines, which are effective in protecting against only EV-A71-associated HFMD infections [
6], have been licensed in China [
7]. However, the dominant serotypes have shifted to CV-A6 and CV-A10, which the existing vaccines provide no protection against [
6]. The incidence of HFMD remained high even after implementing vaccination measures. In 2018, the incidence rate of HFMD was 169.41/100,000 population; this incidence rate was much higher than those of other notifiable infectious diseases, which ranged from < 0.00/100,000 to 92.31/100,000 [
8].
To understand the transmission characteristics of HFMD, and thereby control the disease, many studies have investigated its risk factors. Meteorological factors, especially the ambient temperature and relative humidity, are the leading causes of negative health consequences [
9‐
11]. Indeed, the heterogeneous findings among several multisite studies demonstrate that location-specific characteristics, such as climate conditions, play important roles in the meteorological factor-HFMD association [
10,
12‐
14]. In addition, epidemiological studies have found a significant impact of air pollution on childhood respiratory diseases, such as asthma [
15,
16]. To date, the short-term effects of air pollution on HFMD incidence have been explored by limited studies, and the findings from different regions are inconsistent. For instance, a study conducted in Ningbo, a coastal city in eastern China, did not find a significant relationship between short-term exposure to particulate matter 10 (PM
10; with a diameter ≤ 10 microns) and HFMD incidence [
17]. In contrast, another study reported an inverted V-shaped pattern described the relationship between PM
10 levels and HFMD incidence in inland Chengdu, a typical basin city in southwestern China [
18]. Similarly, Yu et al. found that short-term exposure to low O
3 concentrations was related to an increased risk of HFMD in Guilin, China [
19]. However, studies in coastal Shenzhen [
20] and Ningbo [
21] revealed generally M-shaped and inverted V-shaped curves, respectively. These inconsistent results might be attributed to the influence of location-specific factors, such as environmental variables. Moreover, studies that have explored the potentially nonlinear relationships between HFMD incidence and short-term exposure to air pollutants have only constructed single-city time-series regressions, limiting the evaluation and explanation of the heterogeneity. Therefore, a multicity analysis that is more appropriate for addressing heterogeneity should be performed to gain a comprehensive understanding of the relationship between air pollution and HFMD incidence.
With the increasing interest in the health effects of climate change, concerns have been raised regarding the joint effects of environmental factors, including climatic variables and air pollution, on health. Epidemiological evidence has suggested that the modification effects of meteorological and air pollution variables on short-term mortality effects is of great value to public health [
22,
23]. Several studies have estimated the modification effects of long-term meteorological indicators on the associations of HFMD incidence with relative humidity and temperature [
10,
13,
24]. However, the health impacts of air pollution on HFMD incidence have been quantified by only exposure-lag-disease associations [
19,
21]. Alternatively, air pollutants are typically controlled for as confounders instead of modifiers [
17,
18]. The potential for long-term air pollution levels to modify the relationships between HFMD incidence and environmental factors (including meteorological and air pollution variables) has been ignored in environmental epidemiological studies thus far. Hence, this study assessed the modification effects of air pollutants on the associations between short-term exposure to environmental factors and HFMD incidence, providing novel insights into the health impacts of air pollution.
Sichuan Province was chosen as the study area for three reasons. First, this province has a highly complex topography, with a distinct basin in the eastern region and a variety of environmental conditions across the prefecture-level cities. Second, the complex topography and unique climatic conditions have markedly reduced the self-cleansing of the atmosphere in the basin region. Due to the frequent and severe air pollution events that persist for long durations, the Sichuan Basin is one of the four most heavily polluted areas in China [
25]. Finally, HFMD incidence in Sichuan Province is high and gradually increasing, which might facilitate the identification of factors that influence health risks and the joint effects of exposures.
This study conducted the first assessment of whether long-term air pollution levels modify the relationships of short-term exposure to climatic variables and air pollution with HFMD incidence using a multisite modeling framework in a typical area with a complex terrain, diverse climatic conditions, and severe air pollution. The first aim of our present study was to estimate the short-term health impacts of meteorological variables (i.e., temperature, relative humidity, and wind velocity) and air pollution (i.e., PM10, SO2, O3, CO, and NO2) on HFMD incidence. The current study also aimed to identify potential modifiers and evaluate the modification effects of long-term air pollution levels.
Discussion
In the present study, we applied a two-stage analysis to characterize the associations of multiple meteorological indicators and air pollutants with HFMD incidence in children, focusing on whether and how long-term air pollution levels modified the associations of short-term exposure to climatic variables and air pollutants with HFMD incidence. To the best of our knowledge, this is the first study to quantify the complex short-term impacts of exposure to multiple air pollutants on HFMD incidence in children with a multicity time-series analysis. Importantly, this study is the first to examine the potential modification effects of long-term air pollution levels on the relationships between environmental variables and HFMD.
Our study revealed that a nonlinear inverted V-shaped pattern described the relationship between temperature and HFMD and that there was a positive correlation between relative humidity and HFMD incidence. Therefore, both high temperature and high relative humidity exert adverse effects on HFMD incidence. These results are consistent with previous studies conducted in other regions. For example, inverted V-shaped patterns that describe the relationship between temperature and HFMD have been reported for Guangdong [
32], Wuhan [
33], and Beijing [
34], and a similar positive association between relative humidity and HFMD has been reported in Southwest China [
24]. Host activity, enterovirus excretion, and the survival time of enteroviruses in vitro might be the important pathways by which meteorological factors affect HFMD incidence.
Among the relationships between air pollutants and HFMD, we found an approximately linear relationship between PM
10 levels and HFMD. Compared with moderate PM
10 concentrations, the risks of HFMD decreased at higher PM
10 concentrations. Several previously proposed theories may explain this phenomenon. Particulate matter is conducive to the attachment of enteroviruses and the transmission of HFMD [
35,
36]. Moreover, particulate matter tends to increase inflammation and therefore exacerbate the susceptibility to viral infectious diseases [
37]. Besides, susceptible people are prone to reduce their outdoor activities or wear masks to protect themselves on high-air pollution days [
38]. However, a study in Ningbo [
17] and a study in Shenzhen [
20] both showed that short-term exposure to PM
10 was not significantly associated with HFMD incidence, in contrast with our results. Ningbo and Shenzhen are typical coastal cities in mainland China, while Sichuan is an inland province. These regions exhibit obvious discrepancies in their economies, climates, and lifestyles. Furthermore, the Sichuan Basin is a heavily polluted area with much higher particulate air pollution than other regions; therefore, we propose that the short-term effects of PM
10 on HFMD are more likely to be identified in this area. In such a heavily polluted area, which is characterized by exposure to high levels of particulate matter, the impact of PM
10 on HFMD incidence cannot be ignored, especially at the medium-range scale.
Although the same set of parameters and components were used to construct the DLNM for each prefecture-level city to eliminate heterogeneity in the model specifications, our results suggest that a moderate proportion of heterogeneity is due to true differences among regions in the short-term impacts of meteorological variables and air pollutants on HFMD. We found that CO and SO
2 levels were important effect modifiers of this relationship that explained some of the heterogeneity. High concentrations of CO and SO
2 reduced the risk of HFMD at low temperatures. Reduced enterovirus activity at low temperatures may decrease the chance of transmission to hosts [
39]. Similarly, self-protection measures, including wearing masks and reducing outdoor activities during periods of high concentrations of CO and SO
2, could also decrease exposure in susceptible children [
38]; therefore, air pollution reinforces the protective effects of low temperatures on HFMD. In addition, we found that the risk of HFMD at high temperatures was enhanced by high CO concentrations. Previous studies have indicated that CO exposure exerts several adverse health impacts, such as inflammation and oxidative damage [
40,
41]. Therefore, an increased risk of HFMD was observed with severe CO exposure. However, after excluding the plateau and mountain regions, we did not find that CO levels significantly modified the relationship between temperature and HFMD. This implies that targeted public health measures considering both direct and indirect pathway of CO and SO
2 on HFMD could reduce the health impacts of temperature according to the specific relationships between temperature and HFMD in the two regions.
In addition to the modification effects of long-term air pollution levels on the association between temperature and HFMD, our results also suggested that high SO
2 concentrations reduced the influence of relative humidity on HFMD, especially when the relative humidity was below the median level. Due to the high water solubility of SO
2, these pollutants are more likely to enter and damage the mucosa of the upper respiratory tract [
42,
43]. The respiratory tract is one of the most important transmission routes of HFMD. Thus, we can reasonably speculate that SO
2 invasion in the body under humid conditions will increase susceptibility to HFMD. Additionally, Sichuan Province consists of complex and unique terrain, with high humidity experienced year-round, especially in the eastern basin. Therefore, even under conditions of low and moderate humidity, this phenomenon may be easily observed. However, SO
2 is consumed under higher air-humidity conditions, and the modification effects of SO
2 on the relationship between high relative humidity and HFMD weakens and becomes nonsignificant under such conditions. In addition, at low wind speeds, the relationship between wind speed and HFMD shifted from a positive linear relationship to a generally negative linear relationship in the presence of low and high CO levels, respectively. On low-air pollution days with a wind speed within the comfortable range, children are likely to participate in outdoor activities; wind will accelerate the spread of enteroviruses through airborne droplets [
44,
45]. The complex impacts of various air pollution indicators and meteorological factors on HFMD are generally caused by several underlying mechanisms, which have yet to be revealed. In summary, these findings suggest that in areas exposed to different long-term concentrations of CO and SO
2, public health policies (e.g., reducing ambient air pollution, increasing mask wearing and staying indoors) should consider the modification effects of long-term air pollution levels to reduce the adverse health impacts of meteorological factors on HFMD incidence.
Although this study provides new insights into the short-term effects of environmental factors on HFMD incidence and the potential modification effects of long-term air pollution levels, several limitations should be noted. First, due to the nature of this ecological study, we obtained associations at the population level, which limits causal inference. Second, a considerable part of the heterogeneity was not explained by air pollutant levels. Other variables, such as public health interventions, individual self-protection measures, and customs, may also be potential modifiers; however, these variables are difficult to explore due to the lack of data accessibility. Our results indicate that air pollution also plays a major part in the relationships between environmental factors and HFMD as an effect modifier. These results are highly important for determining the combined effects of multiple factors to formulate more sophisticated and effective public health strategies to protect vulnerable populations from HFMD.
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